Pyrrolo[2,3-b]pyridin-4-yl-amines and pyrrolo[2,3-b]pyrimidin-4-yl-amines as janus kinase inhibitors

ABSTRACT

The present invention provides pyrrolo[2,3-b]pyridine-4-yl amines pyrrolo[2,3-b]pyrimidin-4-yl amines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases and cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Ser. Nos. 60/638,474, filedDec. 22, 2004, and 60/726,289, filed Oct. 13, 2005, the disclosures ofeach of which are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention provides pyrrolo[2,3-b]pyridine-4-yl amines andpyrrolo[2,3-b]pyrimidin-4-yl amines that modulate the activity of Januskinases and are useful in the treatment of diseases related to activityof Janus kinases including, for example, immune-related diseases, skindisorders, and cancer.

BACKGROUND OF THE INVENTION

The immune system responds to injury and threats from pathogens.Cytokines are low-molecular weight polypeptides or glycoproteins thatstimulate biological responses in virtually all cell types. For example,cytokines regulate many of the pathways involved in the hostinflammatory response to sepsis. Cytokines influence celldifferentiation, proliferation and activation, and they can modulateboth proinflammatory and anti-inflammatory responses to allow the hostto react appropriately to pathogens.

Binding of a cytokine to its cell surface receptor initiatesintracellular signaling cascades that transduce the extracellular signalto the nucleus, ultimately leading to changes in gene expression. Thepathway involving the Janus kinase family of protein tyrosine kinases(JAKs) and Signal Transducers and Activators of Transcription (STATs) isengaged in the signaling of a wide range of cytokines. Generally,cytokine receptors do not have intrinsic tyrosine kinase activity, andthus require receptor-associated kinases to propagate a phosphorylationcascade. JAKs fulfill this function. Cytokines bind to their receptors,causing receptor dimerization, and this enables JAKs to phosphorylateeach other as well as specific tyrosine motifs within the cytokinereceptors. STATs that recognize these phosphotyrosine motifs arerecruited to the receptor, and are then themselves activated by aJAK-dependent tyrosine phosphorylation event. Upon activation, STATsdissociate from the receptors, dimerize, and translocate to the nucleusto bind to specific DNA sites and alter transcription (Scott, M. J., C.J. Godshall, et al. (2002). “Jaks, STATs, Cytokines, and Sepsis.” ClinDiagn Lab Immunol 9(6): 1153-9).

The JAK family plays a role in the cytokine-dependent regulation ofproliferation and function of cells involved in immune response.Currently, there are four known mammalian JAK family members: JAK1 (alsoknown as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3(also known as Janus kinase, leukocyte; JAKL; L-JAK and Janus kinase-3)and TYK2 (also known as protein-tyrosine kinase 2). The JAK proteinsrange in size from 120 to 140 kDa and comprise seven conserved JAKhomology (JH) domains; one of these is a functional catalytic kinasedomain, and another is a pseudokinase domain potentially serving aregulatory function and/or serving as a docking site for STATs (Scott,Godshall et al. 2002, supra).

While JAK1, JAK2 and TYK2 are ubiquitously expressed, JAK3 is reportedto be preferentially expressed in natural killer (NK) cells and notresting T cells, suggesting a role in lymphoid activation (Kawamura, M.,D. W. McVicar, et al. (1994). “Molecular cloning of L-JAK, a Janusfamily protein-tyrosine kinase expressed in natural killer cells andactivated leukocytes.” Proc Natl Acad Sci USA 91(14): 6374-8).

Not only do the cytokine-stimulated immune and inflammatory responsescontribute to normal host defense, they also play roles in thepathogenesis of diseases: pathologies such as severe combinedimmunodeficiency (SCID) arise from hypoactivity and suppression of theimmune system, and a hyperactive or inappropriate immune/inflammatoryresponse contributes to the pathology of autoimmune diseases such asrheumatoid and psoriatic arthritis, asthma and systemic lupuserythematosus, as well as illnesses such as scleroderma andosteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000). “Janus kinasesand signal transducers and activators of transcription: their roles incytokine signaling, development and immunoregulation.” Arthritis Res2(1): 16-32). Furthermore, syndromes with a mixed presentation ofautoimmune and immunodeficiency disease are quite common (Candotti, F.,L. Notarangelo, et al. (2002). “Molecular aspects of primaryimmunodeficiencies: lessons from cytokine and other signaling pathways.”J Clin Invest 109(10): 1261-9). Thus, therapeutic agents are typicallyaimed at augmentation or suppression of the immune and inflammatorypathways, accordingly.

Deficiencies in expression of JAK family members are associated withdisease states. Jak1−/− mice are runted at birth, fail to nurse, and dieperinatally (Rodig, S. J., M. A. Meraz, et al. (1998). “Disruption ofthe Jak1 gene demonstrates obligatory and nonredundant roles of the Jaksin cytokine-induced biologic responses.” Cell 93(3): 373-83). Jak2−/−mouse embryos are anemic and die around day 12.5 postcoitum due to theabsence of definitive erythropoiesis. JAK2-deficient fibroblasts do notrespond to IFNgamma, although responses to IFNalpha/beta and IL-6 areunaffected. JAK2 functions in signal transduction of a specific group ofcytokine receptors required in definitive erythropoiesis (Neubauer, H.,A. Cumano, et al. (1998). Cell 93(3): 397-409; Parganas, E., D. Wang, etal. (1998). Cell 93(3): 385-95.). JAK3 appears to play a role in normaldevelopment and function of B and T lymphocytes. Mutations of JAK3 arereported to be responsible for autosomal recessive severe combinedimmunodeficiency (SCID) in humans (Candotti, F., S. A. Oakes, et al.(1997). “Structural and functional basis for JAK3-deficient severecombined immunodeficiency.” Blood 90(10): 3996-4003).

The JAK/STAT pathway, and in particular all four members of the JAKfamily, are believed to play a role in the pathogenesis of the asthmaticresponse. The inappropriate immune responses that characterize asthmaare orchestrated by a subset of CD4+ T helper cells termed T helper 2(Th2) cells. Signaling through the cytokine receptor IL-4 stimulatesJAK1 and JAK3 to activate STAT6, and signaling through IL-12 stimulatesactivation of JAK2 and TYK2, and subsequent phosphorylation of STAT4.STAT4 and STAT6 control multiple aspects of CD4+ T helper celldifferentiation (Pernis, A. B. and P. B. Rothman (2002). “JAK-STATsignaling in asthma.” J Clin Invest 109(10): 1279-83). Furthermore,TYK2-deficient mice were found to have enhanced Th2 cell-mediatedallergic airway inflammation (Seto, Y., H. Nakajima, et al. (2003).“Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficientmice.” J Immunol 170(2): 1077-83).

The JAK/STAT pathway, and in particular, JAK3, also plays a role incancers of the immune system. In adult T cell leukemia/lymphoma (ATLL),human CD4+ T cells acquire a transformed phenotype, an event thatcorrelates with acquisition of constitutive phosphorylation of JAKs andSTATs. Furthermore, an association between JAK3 and STAT-1, STAT-3, andSTAT-5 activation and cell-cycle progression was demonstrated by bothpropidium iodide staining and bromodeoxyuridine incorporation in cellsof four ATLL patients tested. These results imply that JAK/STATactivation is associated with replication of leukemic cells and thattherapeutic approaches aimed at JAK/STAT inhibition may be considered tohalt neoplastic growth (Takemoto, S., J. C. Mulloy, et al. (1997).“Proliferation of adult T cell leukemia/lymphoma cells is associatedwith the constitutive activation of JAK/STAT proteins.” Proc Natl AcadSci USA 94(25): 13897-902).

Blocking signal transduction at the level of the JAK kinases holdspromise for developing treatments for human cancers. Cytokines of theinterleukin 6 (IL-6) family, which activate the signal transducer gp130,are major survival and growth factors for human multiple myeloma (MM)cells. The signal transduction of gp130 is believed to involve JAK1,JAK2 and Tyk2 and the downstream effectors STAT3 and themitogen-activated protein kinase (MAPK) pathways. In IL-6-dependent MMcell lines treated with the JAK2 inhibitor tyrphostin AG490, JAK2 kinaseactivity and ERK2 and STAT3 phosphorylation were inhibited. Furthermore,cell proliferation was suppressed and apoptosis was induced (De Vos, J.,M. Jourdan, et al. (2000). “JAK2 tyrosine kinase inhibitor tyrphostinAG490 downregulates the mitogen-activated protein kinase (MAPK) andsignal transducer and activator of transcription (STAT) pathways andinduces apoptosis in myeloma cells.” Br J Haematol 109(4): 823-8).However, in some cases, AG490 Can induce dormancy of tumor cells andactually then protect them from death.

Pharmacological targeting of Janus kinase 3 (JAK3) has been employedsuccessfully to control allograft rejection and graft versus hostdisease (GVHD). In addition to its involvement in signaling of cytokinereceptors, JAK3 is also engaged in the CD40 signaling pathway ofperipheral blood monocytes. During CD40-induced maturation of myeloiddendritic cells (DCs), JAK3 activity is induced, and increases incostimulatory molecule expression, IL-12 production, and potentallogeneic stimulatory capacity are observed. A rationally designed JAK3inhibitor WHI-P-154 prevented these effects arresting the DCs at animmature level, suggesting that immunosuppressive therapies targetingthe tyrosine kinase JAK3 may also affect the function of myeloid cells(Saemann, M. D., C. Diakos, et al. (2003). “Prevention of CD40-triggereddendritic cell maturation and induction of T-cell hyporeactivity bytargeting of Janus kinase 3.” Am J Transplant 3(11): 1341-9). In themouse model system, JAK3 was also shown to be an important moleculartarget for treatment of autoimmune insulin-dependent (type 1) diabetesmellitus. The rationally designed JAK3 inhibitor JANEX-1 exhibitedpotent immunomodulatory activity and delayed the onset of diabetes inthe NOD mouse model of autoimmune type 1 diabetes (Cetkovic-Cvrlje, M.,A. L. Dragt, et al. (2003). “Targeting JAK3 with JANEX-1 for preventionof autoimmune type 1 diabetes in NOD mice.” Clin Immunol 106(3):213-25).

It has been suggested that inhibition of JAK2 tyrosine kinase can bebeneficial for patients with myeloproliferative disorder. (Levin, etal., Cancer Cell, vol. 7, 2005: 387-397) Myeloprofiferative disorder(MPD) includes polycythemia vera (PV), essential thrombocythemia (ET),myeloid metaplasia with myelofibrosis (MMM), chronic myelogenousleukemia (CML), chronic myelomonocytic leukemia (CMML),hypereosinophilic syndrome (HES) and systemic mast cell disease (SMCD).Although the myeloproliferative disorder (such as PV, ET and MMM) arethought to be caused by acquired somatic mutation in hematopoieticprogenitors, the genetic basis for these diseases has not been known.However, it has been reported that hematopoietic cells from a majorityof patients with PV and a significant number of patients with ET and MMMpossess a recurrent somatic activing mutation in the JAK2 tyrosinekinase. It has also been reported that inhibition of the JAK2V617Fkinase with a small molecule inhibtor leads to inhibition ofproliferation of hematopoietic cells, suggesting that the JAK2 tyrosinekinase is a potential target for pharmacologic inhibition in patientswith PV, ET and MMM.

Inhibition of the Jak kinases is also envisioned to have therapeuticbenefits in patients suffering from skin immune disorders such aspsoriasis, and skin sensitization. In psoriasis vulgaris, the mostcommon form of psoriasis, it has been generally accepted that activatedT lymphocytes are important for the maintenance of the disease and itsassociated psoriatic plaques (Gottlieb, A. B., et al, Nat Rev DrugDisc., 4:19-34). Psoriatic plaques contain a significant immuneinfiltrate, including leukocytes and monocytes, as well as multipleepidermal layers with increased keratinocyte proliferation. While theinitial activation of immune cells in psoriasis occurs by an ill definedmechanism, the maintenance is believed to be dependent on a number ofinflammatory cytokines, in addition to various chemokines and growthfactors (JCI, 113:1664-1675). Many of these, including interleukins -2,-4, -6, -7, -12, -15, -18, and -23 as well as GM-CSF and IFNg, signalthrough the Janus (Jak) kinases (Adv Pharmacol. 2000; 47:113-74). Assuch, blocking signal transduction at the level of Jak kinases mayresult in therapeutic benefits in patients suffering from psoriasis orother immune disorders of the skin.

It has been known that certain therapeutics can cause immune reactionssuch as skin rash or diarrhea in some patients. For instance,administration of some of the new targeted anti-cancer agents such asIressa, Erbitux, and Tarceva has induced acneiform rash with somepatients. Another example is that some therapeutics used topicallyinduce skin irritation, skin rash, contact dermatitis or allergiccontact sensitization. For some patients, these immune reactions may bebothersome, but for others, the immune reactions such as rash ordiarrhea may result in inability to continue the treatment. Although thedriving force behind these immune reactions has not been elucidatedcompletely at the present time, these immune reactions are certainlylinked to immune infiltrate. In light of JAK/STAT pathway, it has alsobeen envisioned that inhibition of the Jak kinases, such as topical orsystemic administration of a Jak inhibitor, may prevent or amelioratethe side effects of immune reactions (skin irritation, skin rash,contact dermatitis, allergic contact sensitization, or diarrhea) causedby some other therapeutics. The Jak inhibitor can be administeredbefore, during or after the treatment of the other therapeutics toprevent or lessen the side effects.

Inhibitors of Janus kinases or related kinases are widely sought andseveral publications report effective classes of compounds. For example,certain inhibitors are reported in US 2004/0198737; WO 2004/099204; WO2004/099205; and WO 01/42246.

Thus, new or improved agents which inhibit Janus kinases are continuallyneeded that act as immunosuppressive agents for organ transplants, aswell as agents for the prevention and treatment of autoimmune diseases(e.g., multiple sclerosis, rheumatoid arthritis, asthma, type Idiabetes, inflammatory bowel disease, Crohn's disease, autoimmunethyroid disorders, Alzheimer's disease), diseases involving ahyperactive inflammatory response (e.g., eczema), allergies, cancer(e.g., prostate, leukemia, multiple myeloma), and some immune reactions(e.g., skin rash or contact dermatitis or diarrhea) caused by othertherapeutics. The compounds, compositions and methods described hereinare directed toward these and other ends.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formulas I and II:

or pharmaceutically acceptable salt forms or prodrugs thereof, whereinconstituent members are provided hereinbelow.

The present invention further provides compositions comprising Formula Iand a pharmaceutically acceptable carrier.

The present invention further provides methods of modulating an activityof JAK comprising contacting JAK with a compound of Formula I.

The present invention further provides methods of treating a disease ina patient, where the disease is associated with JAK activity, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula I.

The present invention further provides compositions for topicaladministration where the compositions comprise a compound of Formula IIand a pharmaceutically acceptable carrier.

The present invention further provides methods of treating skindisorders in a patient by topically administering a therapeuticallyeffective amount of a compound of Formula II.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows systemic and topical activity of a JAK inhibitor in themurine DTH model for dermatitis.

FIG. 2 shows data of the inhibition by a JAK inhibitor oftranscriptional changes associated with immune challenged ears in themurine model of DTH.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds of Formula I:

or pharmaceutically acceptable salt forms or prodrug thereof, wherein:

R¹, R², and R³ are each, independently, H, halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), orS(O)₂NR^(c)R^(d);

R⁴ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, S(O)₂R⁹, SOR⁹,cycloalkyl, or heterocycloalkyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, cycloalkyl, heterocycloalkyl are each optionallysubstituted with 1, 2 or 3 substituents selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

R⁵ is 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -L-(3-8membered cycloalkyl), -L-(3-8 membered heterocycloalkyl), eachsubstituted by one R⁶ and 0, 1 or 2 R⁷;

L is C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S, NR¹⁴, CO,COO, OCO, NR¹⁴C(O)O, CONR¹⁴, SO, SO₂, SONR¹⁴, SO₂NR¹⁴, or NR¹⁴CONR¹⁴;

R⁶ is —W¹—W²—W³—W⁴—W⁵—W⁶—R¹³;

W¹ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substitutedby 1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄alkyl), C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino;

W² is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S,NR¹², CO, COO, OCO, C(S), C(S)NR¹², —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO,SO₂, SONR¹², SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl, C₂₋₄alkenylenyl, C₂₋₄ alkynylenyl, are each optionally substituted by 1, 2or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino orC₂₋₈ dialkylamino;

W³ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO₂,OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino;

W⁴ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S,NR¹², CO, COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹²,SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl,C₂₋₄ alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, CN,NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino;

W⁵ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO₂,OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino;

W⁶ is absent, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, O, S, NR¹², CO,COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹², SO₂NR¹², orNR¹²CONR¹², wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl are eachoptionally substituted by 1, 2 or 3 CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄alkylamino or C₂₋₈ dialkylamino;

R⁷ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆alkyl)-SR^(a″), —(C₁₋₆alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆alkyl)-S(O)₂R^(b″), or —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″);

R⁹ is C₁₋₄ alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl,each optionally substituted with 1, 2, or 3 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′),C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′),OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′),NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), andS(O)₂NR^(c′)R^(d′);

R¹² and R¹⁴ are each, independently, H or C₁₋₆ alkyl optionallysubstituted by 1, 2 or 3 substituents selected from OH, CN, NO₂, amino,(C₁₋₄ alkyl)amino, (C₂₋₈ dialkyl)amino, C₁₋₆ haloalkyl, C₁₋₆ acyl, C₁₋₆acyloxy, C₁₋₆ acylamino, —(C₁₋₆ alkyl)-CN, and —(C₁₋₆ alkyl)-NO₂;

R¹³ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), or —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″), wherein each of said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from:

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)—S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″);

R^(a), R^(a′) and R^(a″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl;

R^(b), R^(b′) and R^(b″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl;

R^(c) and R^(d) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(c′) and R^(d′) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl;

or R^(c′) and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and

R^(c″) and R^(d″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl;

or R^(c″) and R^(d″) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group.

The present invention further provides compounds of Formula II:

or pharmaceutically acceptable salt forms or prodrugs thereof, wherein:

A is N or CR¹;

R¹, R², and R³ are each, independently, H, halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), orS(O)₂NR^(c)R^(d);

R⁴ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, S(O)₂R⁹, SOR⁹,cycloalkyl, or heterocycloalkyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, cycloalkyl, heterocycloalkyl are each optionallysubstituted with 1, 2 or 3 substituents selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

R⁵ is 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -L-(3-8membered cycloalkyl), -L-(3-8 membered heterocycloalkyl), eachsubstituted by one R⁶ and 0, 1 or 2 R⁷;

L is C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S, NR¹⁴, CO,COO, OCO, NR¹⁴C(O)O, CONR¹⁴, SO, SO₂, SONR¹⁴, SO₂NR¹⁴, or NR¹⁴CONR¹⁴;

R⁶ is —W¹—W²—W³ W⁴—W⁵—W⁶—R¹³;

W¹ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substitutedby 1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino;

W² is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S,NR¹², CO, COO, OCO, C(S), C(S)NR¹², —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO,SO₂, SONR¹², SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl, C₂₋₄alkenylenyl, C₂₋₄ alkynylenyl, are each optionally substituted by 1, 2or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino orC₂₋₈ dialkylamino;

W³ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO₂,OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino;

W⁴ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S,NR¹², CO, COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹²,SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl,C₂₋₄ alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, CN,NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino;

W⁵ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO₂,OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino;

W⁶ is absent, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, O, S, NR¹², CO,COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹², SO₂NR¹², orNR¹²CONR¹², wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl are eachoptionally substituted by 1, 2 or 3 CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄alkyl), C₂₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄alkylamino or C₂₋₈ dialkylamino;

R⁷ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″),—(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), or—(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″);

R⁹ is C₁₋₄ alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl,each optionally substituted with 1, 2, or 3 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a′), SR^(a′),C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′),OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′),NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), andS(O)₂NR^(c′)R^(d′);

R¹² and R¹⁴ are each, independently, H or C₁₋₆ alkyl optionallysubstituted by 1, 2 or 3 substituents selected from OH, CN, NO₂, amino,(C₁₋₄ alkyl)amino, (C₂₋₈ dialkyl)amino, C₁₋₆ haloalkyl, C₁₋₆ acyl, C₁₋₆acyloxy, C₁₋₆ acylamino, —(C₁₋₆ alkyl)-CN, and —(C₁₋₆ alkyl)-NO₂;

R¹³ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆alkyl)-SR^(a″), (C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″),—(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), or —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″), wherein each of said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from:

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″);

R^(a), R^(a′) and R^(a″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl;

R^(b), R^(b′) and R^(b″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl;

R^(c) and R^(d) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(c′) and R^(d′) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl;

or R^(c′) and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and

R^(c″) and R^(d″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl;

or R^(c″) and R^(d″) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group.

In some embodiments, A is CR¹.

In some embodiments, A is N.

In some embodiments, R¹ is H.

In some embodiments, R² is H.

In some embodiments, R³ is H.

In some embodiments, R⁴ is H or C₁₋₄ alkyl.

In some embodiments, R⁴ is methyl.

In some embodiments, R⁵ is 3-8 membered heterocycloalkyl substituted byone R⁶ and 0, 1 or 2R⁷.

In some embodiments, R⁵ is 6-membered heterocycloalkyl substituted byone R⁶ and 0, 1 or 2R⁷.

In some embodiments, R⁵ is piperidinyl substituted by one R⁶ and 0, 1 or2 R⁷.

In some embodiments, R⁵ is piperidin-3-yl substituted by one R⁶ and 0, 1or 2 R⁷.

In some further embodiments, R⁶ is substituted on the piperidinylN-atom.

In some embodiments, R⁵ is -L-pyrrolidinyl; L is C₁₋₄ alkylenyl; and thepyrrolidinyl is substituted by one R⁶ and 0, 1 or 2 R⁷.

In some embodiments, R⁵ is -L-pyrrolidin-2-yl; L is C₁₋₄ alkylenyl andthe pyrrolidin-2-yl is substituted by one R⁶ and 0, 1 or 2 R⁷.

In some embodiments, W² is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl,C₂₋₄ alkynylenyl, O, S, NR¹², CO, COO, OCO, —C(═N—CN)—, NR¹²C(O)O,CONR¹², SO, SO₂, SONR¹², SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, are each optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, and C₂₋₈dialkylamino.

In some embodiments, W² is SO₂, CO, COO, C(S)NR¹², or CONR¹².

In some embodiments, W² is SO₂, CO, COO, C(S)NH, CONH or —CON(C₁₋₄alkyl)-.

In some embodiments, W² is SO₂ or CO.

In some embodiments, W³ is C₁₋₄ alkylenyl or cycloalkyl.

In some embodiments, R¹³ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN,NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″),—(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″),—(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), or—(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″).

In some embodiments, R¹³ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from:

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆alkyl)SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″),—(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″),(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″).

In some embodiments, R¹³ is aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from:

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″).

In some embodiments, R¹³ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by1, 2, 3, 4 or 5 substituents independently selected from:

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″).

In some embodiments, R¹³ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by1, 2, 3, 4 or 5 substituents independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, aryl, heteroaryl, halo, CN, OR^(a″), SR^(a″),C(O)R^(b″), C(O)OR^(a″), NR^(c″)C(O)R^(d″), S(O)₂R^(b″), and —(C₁₋₆alkyl)-CN.

In some embodiments, R¹³ is aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, heteroaryl, halo, CN, OR^(a″), SR^(a″), C(O)R^(b″), C(O)OR^(a″),NR^(c″)C(O)R^(d″), S(O)₂R^(b″), and —(C₁₋₆ alkyl)-CN.

In some embodiments, R¹³ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by1, 2, 3, 4 or 5 substituents independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, aryl, heteroaryl, halo, CN, OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, heteroaryloxy, aryloxy, —SC₁₋₆ alkyl, —C(O)—C₁₋₆ alkyl,—C(O)OC₁₋₆ alkyl, —S(O)₂C₁₋₆ alkyl, —NHC(O)—C₁₋₆ alkyl, and —(C₁₋₆alkyl)-CN.

In some embodiments, R¹³ is aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, heteroaryl, halo, CN, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,heteroaryloxy, aryloxy, —SC₁₋₆ alkyl, —C(O)—C₁₋₆ alkyl, —C(O)OC₁₋₆alkyl, —S(O)₂C₁₋₆ alkyl, —NHC(O)—C₁₋₆ alkyl, and —(C₁₋₆ alkyl)-CN.

In some embodiments, R¹³ is aryl, cycloalkyl, heteroaryl orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, heteroaryl, halo, CN, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,heteroaryloxy, aryloxy, —SC₁₋₆ alkyl, —C(O)—C₁₋₆ alkyl, —C(O)OC₁₋₆alkyl, —S(O)₂C₁₋₆ alkyl, —NHC(O)—C₁₋₆ alkyl, and —(C₁₋₆ alkyl)-CN.

In some embodiments, R¹³ is arylalkyl, cycloalkylalkyl, heteroarylalkylor heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, heteroaryl, halo, CN, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,heteroaryloxy, aryloxy, —SC₁₋₆ alkyl, —C(O)—C₁₋₆ alkyl, —C(O)OC₁₋₆alkyl, —S(O)₂C₁₋₆ alkyl, —NHC(O)—C₁₋₆ alkyl, and —(C₁₋₆ alkyl)-CN.

In some embodiments, R¹³ is OH or CN.

In some embodiments, W¹ is absent, W² is CO or SO₂, W³ is C₁₋₄alkyleneyl or cycloalkyl, W⁴ is absent, W⁵ is absent, W⁶ is absent, andR¹³ is CN or OH.

In some embodiments, R⁶ is —W²—W³—R³.

In some embodiments, R⁶ is —CO—CH₂—CN.

In some embodiments, R⁶ is —W²—R¹³.

In some embodiments, R⁶ is R¹³.

In some embodiments:

R⁶ is —W²—R¹³;

W² is SO₂, CO, COO, C(S)NR¹², or CONR¹²; and

R¹³ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from:

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″).

In some embodiments, the compounds of formula I of the present inventionhave the structure of Formula I-A:

wherein t is 0, 1 or 2.

In some embodiments, the compounds of the invention have Formula I-Awherein:

W² is SO₂, CO, COO, C(S)NR¹², or CONR¹²;

R¹³ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from:

C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″)—(C₁₋₆ alkyl)-C(O)R^(b″)-(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″); and

t is 0, 1 or 2.

In some embodiments, t is 0.

In some embodiments, t is 1.

In some embodiments, t is 2.

In some embodiments, the compounds of the present invention have thestructure of Formula I-B:

wherein t1 is 0 or 1.

In some further embodiments, the compounds of the invention have FormulaI-B wherein:

R¹³ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, heteroaryl, halo, CN, OR^(a″), SR^(a″), C(O)R^(b″), C(O)OR^(a″),NR^(c″)C(O)R^(d″), S(O)₂R^(b″), and —(C₁₋₆ alkyl)-CN;

W² is SO₂, CO, COO, C(S)NH, CONH or —CON(C₁₋₄ alkyl)-; and

R⁴ is C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, S(O)₂R⁹, SOR⁹, cycloalkyl,or heterocycloalkyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, cycloalkyl, heterocycloalkyl are each optionally substitutedwith 1, 2 or 3 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, t1 is 0.

In some embodiments, t1 is 1.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety selected from the Markushgroup defining the variable. For example, where a structure is describedhaving two R groups that are simultaneously present on the samecompound; the two R groups can represent different moieties selectedfrom the Markush group defined for R.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms. The term “alkylenyl” refers to a bivalent alkyl group.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, cyclohexenyl, and the like. The term “alkenylenyl” refers to abivalent alkenyl group.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like. The term “alkynylenyl” referes to a bivalentalkynyl group.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 20 Carbonatoms.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)ring systems. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, for example, benzo derivatives ofpentane, pentene, hexane, and the like. One or more ring-forming carbonatoms of a cycloalkyl group can be oxidized, for example, having an oxoor sulfido substituent. Example cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl,norcamyl, adamantyl, and the like.

As used herein, “heteroaryl” groups refer to an aromatic heterocyclehaving at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g.,having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in aheteroaryl group can also be oxidized to form an N-oxo moiety. Examplesof heteroaryl groups include without limitation, pyridyl, N-oxopyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl,isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and thelike. In some embodiments, the heteroaryl group has from 1 to about 20Carbon atoms, and in further embodiments from about 3 to about 20 Carbonatoms. In some embodiments, the heteroaryl group contains 3 to about 14,3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, theheteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to non-aromatic heterocyclescontaining at least one ring-forming heteroatom such as an O, N, or Satom. Heterocycloalkyl groups can include mono- or polycyclic (e.g.,having 2, 3 or 4 fused rings) ring systems. Any ring-forming heteroatomor ring-forming carbon atom of a heterocycloalkyl group can also beoxidized by one or two oxo or sulfido substituents. Example“heterocycloalkyl” groups include morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl,and benzo derivatives of heterocycles such as indolene and isoindolenegroups. In some embodiments, the heterocycloalkyl group has from 1 toabout 20 Carbon atoms, and in further embodiments from about 3 to about20 Carbon atoms. In some embodiments, the heterocycloalkyl groupcontains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. Insome embodiments, the heterocycloalkyl group has 1 to about 4, 1 toabout 3, or 1 to 2 heteroatoms. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used here, “haloalkoxy” refers to an —O-haloalkyl group. An examplehaloalkoxy group is OCF₃.

As used herein, “aryloxy” refers to an —O-aryl group. An example aryloxygroup is phenoxy.

As used herein, “heteroaryloxy” refers to an —O-heteroaryl group. Anexample heteroaryloxy group is pyridin-2-yloxy or pyridin-3-yloxy.

As used herein, “amino” refers to NH₂.

As used herein, “alkylamino” refers to an amino group substituted by analkyl group.

As used herein, “dialkylamino” refers to an amino group substituted bytwo alkyl groups.

As used herein, “arylalkyl” refers to an alkyl group substituted by anaryl group.

As used herein, “heteroarylalkyl” refers to an alkyl group substitutedby a heteroaryl group.

As used herein, “cycloalkylalkyl” refers to an alkyl group substitutedby a cycloalkyl group.

As used herein, “heterocycloalkylalkyl” refers to an alkyl groupsubstituted by a heterocycloalkyl group.

As used herein, “acyl” refers to —C(O)-alkyl.

As used herein, “acyloxy” refers to —OC(O)-alkyl.

As used herein, “acylamino” refers to an amino group substituted with anacyl group.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms, such asketo-enol tautomers.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds describedherein. As used herein, “prodrugs” refer to any covalently bondedcarriers which release the active parent drug when administered to amammalian subject. Prodrugs can be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxyl, amino,sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated by referencein their entirety.

Synthesis

Compounds of the invention, including salts, hydrates, and solvatesthereof, can be prepared using known organic synthesis techniques andcan be synthesized according to any of numerous possible syntheticroutes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Green and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C)infrared spectroscopy, spectrophotometry (e.g., UV-visible), or massspectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

Compounds of the invention can be prepared according to numerouspreparatory routes known in the literature. Example synthetic methodsfor preparing compounds of the invention are provided in the Schemesbelow.

Scheme 1 shows an example synthesis of compounds of the inventionstarting with pyrrolo[2,3-b]pyridines 1-1 from which the N-oxo analog(1-2) is made by treatment with an oxidant such as m-CPBA. The N-oxide1-2 can be halogenated with a halogenating agent such as MeSO₂Cl, toform a 4-halo compound 1-3 (Y is halo such as Cl). The 4-amino compoundsof the invention (1-4) can be generated by treatment of 1-3 with anappropriate amine (NHR⁴R⁵), optionally in the presence of heat. In someinstances, the pyrrolo amine of 1-3 can be protected with a suitableamino protecting group prior to reaction with NHR⁴R⁵, and the aminoprotecting group can be removed after the reaction with NHR⁴R⁵.

Scheme 2 provides an example synthesis of compounds of the inventionwhere R⁵ is piperidin-3-yl. A 4-chloro compound 2-1 (wherein the pyrroloamine group can optionally be protected by an appropriate aminoprotecting group; in cases where the pyrrolo amine group is protected,the protecting group can be removed in a later stage), can be treatedwith a protected piperidine 2-2 to form a 4-piperidine compound 2-3. Theprotecting group at the N-atom on the piperidine moiety of 2-3 can beremoved by routine methods (e.g., hydrogenation in the presence of Pdcatalyst and HCl to remove benzyl protecting group) to form a compound2-4. Alkylation or acylation of the N-atom on the piperidine moiety of2-4 with a reagent such as R⁶—X, where X is a leaving group such ashalo, hydroxyl, mesylate, tosylate, etc., affords a compound 2-5 of theinvention. For example, R⁶—X can be a carboxylic acid, acid chloride,alkyl/aryl sulfonyl chloride, haloalkane, etc.

Methods for preparing pyrrolo[2,3-d]pyrimidines according to theinvention are reported in WO 01/42246, WO 02/00661, and WO 03/48162,each of which is incorporated herein by reference in its entirety.

Methods

Compounds of the invention can modulate activity of one or more Januskinases (JAKs). The term “modulate” is meant to refer to an ability toincrease or decrease the activity of one or more members of the JAKfamily of kinases. Accordingly, compounds of the invention can be usedin methods of modulating a JAK by contacting the JAK with any one ormore of the compounds or compositions described herein. In someembodiments, compounds of the present invention can act as inhibitors ofone or more JAKs. In some embodiments, compounds of the presentinvention can act to stimulate the activity of one or more JAKs. Infurther embodiments, the compounds of the invention can be used tomodulate activity of a JAK in an individual in need of modulation of thereceptor by administering a modulating amount of a compound of theinvention.

JAKs to which the present compounds bind and/or modulate include anymember of the JAK family. In some embodiments, the JAK is JAK1, JAK2,JAK3 or TYK2. In some embodiments, the JAK is JAK1 or JAK2. In someembodiments, the JAK is JAK2.

The compounds of the invention can be selective. By “selective” is meantthat the compound binds to or inhibits a JAK with greater affinity orpotency, respectively, compared to at least one other JAK. In someembodiments, the compounds of the invention are selective inhibitors ofJAK1 or JAK2 over JAK3 and/or TYK2. In some embodiments, the compoundsof the invention are selective inhibitors of JAK2 (e.g., over JAK1, JAK3and TYK2). Without wishing to be bound by theory, because inhibitors ofJAK3 can lead to immunosuppressive effects, a compound which isselective for JAK2 over JAK3 and which is useful in the treatment ofcancer (such as multiple myeloma, for example) can offer the additionaladvantage of having fewer immunosuppressive side effects. Selectivitycan be at least about 5-fold, 10-fold, at least about 20-fold, at leastabout 50-fold, at least about 100-fold, at least about 200-fold, atleast about 500-fold or at least about 1000-fold. Selectivity can bemeasured by methods routine in the art. In some embodiments, selectivitycan be tested at the Km of each enzyme. In some embodiments, selectivityof compounds of the invention for JAK2 over JAK3 can be determined bythe cellular ATP concentration.

Another aspect of the present invention pertains to methods of treatinga JAK-associated disease or disorder in an individual (e.g., patient) byadministering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof. A JAK-associateddisease can include any disease, disorder or condition that is directlyor indirectly linked to expression or activity of the JAK, includingoverexpression and/or abnormal activity levels. A JAK-associated diseasecan also include any disease, disorder or condition that can beprevented, ameliorated, or cured by modulating JAK activity.

Examples of JAK-associated diseases include diseases involving theimmune system including, for example, organ transplant rejection (e.g.,allograft rejection and graft versus host disease). Further examples ofJAK-associated diseases include autoimmune diseases such as multiplesclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes,lupus, psoriasis, inflammatory bowel disease, ulcerative colitis,Crohn's disease, or autoimmune thyroid disorders. Further examples ofJAK-associated diseases include allergic conditions such as asthma, foodallergies, atopic dermatitis and rhinitis. Further examples ofJAK-assoicated diseases include viral diseases such as Epstein BarrVirus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-ZosterVirus (VZV) and Human Papilloma Virus (HPV). Futher examples ofJAK-associated diseases or conditions include skin disorders such asatopic dermatitis, psoriasis (for example, psoriasis vulgaris), skinsensitization, and the like. Further examples of JAK-associated diseasesare those involving IL-6 pathways including Castleman's disease,Kaposi's sarcoma, and others. Futher examples of JAK-associated diseasesor conditions include immune reactions (such as diarrhea, skinirritation, skin rash, contact dermatitis or allergic contactsensitization) caused by certain therapeutics in some patients. Furtherexamples of JAK-associated diseases include hyperpropliferativedisorders including polycythemia vera, essential thrombocytopenia,myeloid metaplasia with myelofibrosis, and the like. In furtherembodiments, the JAK-associated disease is cancer such as, for example,prostate, renal, hepatocellular, pancreatic, gastric, breast, lung,cancers of the head and neck, glioblastoma, leukemia, lymphoma ormultiple myeloma.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a JAK with a compound of the invention includesthe administration of a compound of the present invention to anindividual or patient, such as a human, having a JAK, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the JAK.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes one or more of the following:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology).

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, and/or immunosuppressantscan be used in combination with the compounds of the present inventionfor treatment of JAK-associated diseases, disorders or conditions. Forexample, a JAK inhibitor used in combination with a chemotherapeutic inthe treatment of multiple myeloma may improve the treatment response ascompared to the response to the chemotherapeutic agent alone, withoutexacerbation of its toxic effects. Examples of additional pharmaceuticalagents used in the treatment of multiple myeloma, for example, caninclude, without limitation, melphalan, melphalan plus prednisone [MP],doxorubicin, dexamethasone, and velcade. Additive or synergistic effectsare desirable outcomes of combining a JAK inhibitor of the presentinvention with an additional agent. Furthermore, resistance of multiplemyeloma cells to agents such as dexamethasome may be reversible upontreatment with a JAK inhibitor of the present invention. The agents canbe combined with the present compounds in a single or continuous dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds described herein can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.Coated condoms, gloves and the like may also be useful.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of Formulas I andII above in combination with one or more pharmaceutically acceptablecarriers (excipients). In making the compositions of the invention, theactive ingredient is typically mixed with an excipient, diluted by anexcipient or enclosed within such a carrier in the form of, for example,a capsule, sachet, paper, or other container. When the excipient servesas a diluent, it can be a solid, semi-solid, or liquid material, whichacts as a vehicle, carrier or medium for the active ingredient. Thus,the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, suppositories, sterile injectablesolutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral adminstration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating JAK in tissue samples,including human, and for identifying JAK ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes JAKassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro metalloprotease labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Synthticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a JAK by monitering its concentrationvariation when contacting with the JAK, through tracking of thelabeling. For example, a test compound (labeled) can be evaluated forits ability to reduce binding of another compound which is known to bindto a JAK (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the JAKdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labled and test compounds areunlabeled. Accordingly, the concentration of the labled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of JAK-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound described herein. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to be JAKinhibitors according to at least one biological assay described herein.

EXAMPLES Example 13-{3-[Methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

Step 1. 1H-pyrrolo[2,3-b]pyridine 7-oxide

To a 0° C. solution of 1H-pyrrolo[2,3-b]pyridine (4.90 g, 0.0415 mol) inethyl acetate (41 mL, 0.42 mol) was added a solution ofm-chloroperbenzoic acid (m-cpba 9.3 g, 0.054 mol) in ethyl acetate (27mL, 0.28 mol), and the reaction mixture was solidified when ˜20 mLsolution of the m-cpba was added. An additional ˜10 mL of ethyl acetatewas added to facilitate stirring. The reaction was stirred overnight.The reaction mixture was then cooled to 0° C., filtered and washed withethyl acetate (×3) to give 10.94 g wet solid. To a slurry of 8.45 g ofthe solid in water (35 mL) was added 13 mL of sat. Na₂CO₃ dropwise. Theresulting mixture was stirred slowly overnight, cooled to 0° C.,filtered and washed with water (×4) to give 3.55 g of pale purple solid.The product was dried at 40° C. overnight to give 2.47 g (44.4% yield).

¹H NMR (400 MHz, CD₃OD): δ 8.2 (1H, d); 7.95 (1H, d); 7.5 (1H, d); 7.2(1H, m); 6.65 (1H, d). MS (M+H)⁺: 136.

Step 2: 4-Chloro-1H-pyrrolo[2,3-b]pyridine

To a 50° C. pink solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide (2.47 g,0.0184 mol) in N,N-dimethylformamide (13.3 mL, 0.172 mol) was addedmethanesulfonyl chloride (4.0 mL, 0.052 mol). The pink color changed toorange. The mixture was heated to 73° C. for 2 h, and cooled to 40° C.Then 35 mL of water was added and the resulting suspension was cooled to0° C. NaOH was added to adjust the pH of the mixture to ˜7. The mixturewas filtered and washed with water (×3) to give 3.8 g of wet pale orangesolid that was dried at 40° C. overnight to give 2.35 g (82.2% yield).

¹H NMR (400 MHz, CDCl₃): δ 10.8 (1H, br); 8.21 (1H, d); 7.41(1H, d);7.18 (1H, d); 6.61 (1H, d). MS (M+H)⁺: 153.

Step 3:N-(1-benzylpiperidin-3-yl)-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine

A sealed melted mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.18 g,0.0012 mol) in 1-benzyl-N-methylpiperidin-3-amine (0.50 g, 0.0024 mol)was heated to 200° C. overnight. The reaction mixture was partitionedbetween ethyl acetate (30 mL) and sat. NaHCO₃ (20 mL), and the organicphase was washed with sat. NaCl, then dried and was reduced under vacuumto give 500 mg of orange oil. The product was chromatographed with 7%MeOH/DCM, 0.7% NH₄OH to give 192 mg of an orange oil (48.8% yield).

¹H NMR (400 MHz, CDCl₃): δ 7.98 (1H, d); 7.34 (5H, m); 7.08 (1H, d);6.55 (1H, d); 6.2 (1H, d); 4.15 (1H, t); 3.47 (2H, q); 3.15 (1H); 3.1(3H, s); 2.9 (1H, d) 2.2-1.6 (6H, m). MS (M+H)⁺: 322.

Step 4:N-methyl-N-piperidin-3-yl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-aminetrihydrochloride

A degassed mixture ofN-(1-benzylpiperidin-3-yl)-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine(0.17 g, 0.00053 mol) and palladium hydroxide (0.15 g, 0.00011 mol) inethanol (3.5 mL, 0.060 mol) and 3.0 M of hydrogen chloride in water(0.40 mL) was stirred under an atmosphere of hydrogen over 2.5 days. Thereaction mixture was filtered and washed with MeOH. The filtrate wasconcentrated under vacuum to give 92 mg of orange oil.

¹H NMR (400 MHz, DMSO-d6): δ 12.4 (1H, s);9.39 (2H, br);8.04 (1H, d);7.4 (1H, d); 6.55 (1H, d); 6.95 (1H, d); 6.89 (1H, d); 4.63 (1H, t);3.4-1.8 (11H, m). MS (M+H)⁺: 259.

Step 5:3-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl-3-oxopropanenitrile

To a solution ofN-methyl-N-piperidin-3-yl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-aminetrihydrochloride (0.092 g, 0.00027 mol) in N,N-dimethylformamide (2 mL,0.02 mol) were added N,N-diisopropylethylamine (190 μL, 0.0011 mol),cyanoacetic acid (28 mg, 0.00032 mol), 1-hydroxybenzotriazole (36 mg,0.00027 mol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (62 mg, 0.00032 mol). The mixture was stirred for 2 h. Thereaction mixture was partitioned between ethyl acetate and water and theaqueous phase was extracted with ethyl acetate. The combined organicphases were washed with sat. NaCl, dried and concentrated. The residuewas chromatographed with 5-7% MeOH/DCM, 0.5-0.7% NH₄OH to give 16 mg oforange solid which was triturated with warm acetonitrile. The resultingsolid was filtered and was washed with acetonitrile (×3) to give 9 mg ofoff-white solid that was dried at 40° C. over the weekend.

¹H NMR (400 MHz, DMSO): δ 11.3 (1H, s); 7.85 (1H, d); 7.18 (1H, d); 6.45(1H, m); 6.32 (1H, m); 4.4 (1H, m); 4.1 (2H, m); 3.9 (1H, br); 3.6 (1H,br); 3.0-2.8 (4H, m) 1.92-1.75 (3H, m); 1.7 (1H, m). MS (M+H)⁺: 298.

Example 23-{(3R,4R)-4-Methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

Step 1:4-Chloro-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

To a 0° C. solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.50 g,0.0033 mol) and [β-(trimethylsilyl)ethoxy]methyl chloride (0.75 mL,0.0043 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was added sodiumhydride (0.17 g, 0.0043 mol). The resulting mixture was stirredovernight and partitioned between ethyl acetate and water (×2), and theorganic layer was washed with sat. NaCl. The organic layer was thendried under vacuum to produce 1.05 g of an orange oil which waschromatographed with 15% ethyl acetate/hex to give 830 mg of a colorlessoil (89.6% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.29 (1H, d); 7.48 (1H, d); 7.19 (1H, d); 6.7(1H, d); 5.75 (2H, s); 3.6 (2H, t); 0.98 (2H, t); 0 (9H, s). MS (M+H)⁺:283.

Step 2:N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-1-[2-(trimethylsilyl)-ethoxy]methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine

A degassed mixture of (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine(0.210 g, 0.000962 mol),4-chloro-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.29 g, 0.0010 mol), tris(dibenzylideneacetone)dipalladium(0) (0.088 g,0.000096 mol), 0.049 M of tri-tert-butylphosphine in toluene (1.0 mL)and sodium tert-butoxide (0.139 g, 0.00144 mol) in toluene (3 mL, 0.03mol) was heated to 70° C. for 5 h. After the reaction mixture was cooledto room temperature (rt), ethyl acetate and water were added. Theresulting suspension was filtered. The aqueous phase was removed and theremaining organic phase was washed with sat. NaCl, dried, andconcentrated under vacuum to give 540 mg orange oil. The crude productwas chromatographed using 35% ethyl acetate/hex to give 280 mg orangeoil (˜1:1 of two isomers). The mixture was chromatographed again with35% ethyl acetate/hex several times to separate 44 mg of the higherR_(f) material.

¹H NMR (400 MHz, CDCl₃): δ 8.15 (1H, d); 7.38 (5H, m); 7.18 (1H, d); 6.6(1H, d); 6.3 (1H, d); 5.7 (2H, s); 4.58 (1H, t); 3.6 (4H, m); 3.38 (3H,s); 2.86 (1H, br); 2.79 (1H, br); 2.6 (1H, br); 2.55 (1H, br); 2.4 (1H,br); 1.95 (1H, br); 1.77 (1H, br); 1.02 (3H, d); 0.99 (2H, t); 0 (9H,s). MS (M+H)⁺: 465.

Step 3:N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine

A solution of N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-1-[2-(trimethylsilyl)ethoxy]methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine(0.065 g, 0.00014 mol) in trifluoroacetic acid (0.6 mL, 0.008 mol) andmethylene chloride (3 mL, 0.05 mol) was stirred overnight. The solventvolume was reduced by roto-vap 3× azeotroped with MeOH. The resultingorange oil was stirred in methanol (1.5 mL, 0.037 mol) and 1.00 M ofsodium hydroxide in water (0.5 mL) overnight. Solvents were removedunder vacuum and the remaining solid was stirred in ethyl acetate andwater. The organic phase was washed with sat. NaCl and the solvent wasremoved under vacuum to give 37 mg of an orange oil.

¹H NMR (400 MHz, CDCl₃): δ 8.0 (1H, d); 7.38 (5H, m); 7.1 (1H, d); 6.75(1H, d); 6.2 (1H, d); 4.58 (1H, t); 3.55 (2H, m); 3.3 (3H, s); 2.8 (1H,br); 2.7 (1H, br); 2.55 (1H, br); 2.45 (1H, br); 2.32 (1H, br); 1.9 (1H,br); 1.65 (1H, br); 1.02 (3H, d). MS (M+H)⁺: 335.

Step 4:N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine

A degassed mixture ofN-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine(0.030 g, 0.000090 mol) and palladium (0.028 g, 0.000026 mol) in ethanol(2 mL, 0.03 mol) and 3.0 M of hydrogen chloride in water (0.2 mL) wasstirred under an atmosphere of hydrogen overnight. The reaction mixturewas filtered and washed with MeOH. The solvent was removed under vacuumto give 52 mg of an orange viscous oil. The oil was partitioned betweenethyl acetate and sat. NaHCO₃. The aqueous phase was extracted withethyl acetate and THF. The combined organic phases were washed with sat.NaCl. Solvents were removed under vacuume to give 47 mg of an orangesolid.

¹H NMR (400 MHz, MeOH): δ 7.8 (1H, d); 7.1 (1H, d); 6.6 (1H, d); 6.3(1H, d); 4.45 (1H, m); 3.7 (1H, m); 3.12 (3H, s); 3.4-1.0 (6H, m); 1.1(3H, d). MS (M+H)⁺: 245.

Step 5:3-{(3R,4R)-4-Methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

A mixture ofN-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine(43.0 mg, 0.000176 mol) and3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (38 mg, 0.00021mol) in ethanol (1 mL, 0.02 mol) was stirred overnight. The reactionmixture was partitioned between ethyl acetate/THF and sat. NaHCO₃, andthe organic layer was washed by sat. NaCl. The solvent was removed undervacuum to give 100 mg of an orange solid which was chromatographed with7% MeOH/DCM, 0.7% NH4OH to give 17 mg of pale orange solid. The crudeproduct was triturated with Et₂O and the resulting solid was filteredand washed to give 9.4 mg of wet pale orange solid which was dried atfrom room temperature to about 60° C. for 3.5 h to give 6.5 mg of thefinal product.

¹H NMR (400 MHz, CDCl₃): δ 8.15 (1H, d); 7.17 (1H, d); 6.46 (1H, d); 6.3(1H, d); 4.35 (2H, m); 4.0-3.78 (1H, m); 3.6-3.4 (2H, m); 2.59 (1H, m);1.99-1.75 (3H, m); 1.15 (3H, d). MS (M+H)⁺: 312.

The following additional compounds of the invention in Table 1 were madeby methods analogous to those described for Examples 1 and 2. TABLE 1Ex. No. Structure Name (M + 1) 3

N-methyl-N-[(3R,4R)-4-methyl-1- (phenylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 385.2 4

N-[(3R,4R)-1-(methoxyacetyl)-4- methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 316.2 5

(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]-N-phenylpiperidine-1-carboxamide 364.2 6

(3R,4R)-N-benzyl-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide 378.2 7

(3R,4R)-N-ethyl-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide 316.2 8

(3R,4R)-N-isopropyl-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide 330.2 9

N-[(3R,4R)-1-isobutyryl-4- methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 315.2 10

N-methyl-N-[(3R,4R)-4-methyl-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 358.2 11

N-[(3R,4R)-1-acetyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin- 4-yl)-amine 287.2 12

N-methyl-N-[(3R,4R)-4-methyl-1-(3- methylbutanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 329.2 13

N-[(3R,4R)-1-benzoyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3- b]pyridin-4-yl)-amine 349.2 14

(3R,4R)-N,N,4-trimethyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide 316.2 15

4-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)benzonitrile 374.2 16

N-[(3R,4R)-1-(cyclopropylcarbonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine313.2 17

N-[(3R,4R)-1-isonicotinoyl-4- methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 350.2 18

N-{(3R,4R)-1-[(1-acetylpiperidin-4-yl)carbonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 398.2 19

Phenyl (3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxylate 365.2 20

Methyl (3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxylate 303.2 21

N-methyl-N-[(3R,4R)-4-methyl-1- (trifluoroacetyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 341.2 22

N-[(3R,4R)-1-(2-furoyl)-4- methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 339.2 23

(3R,4R)-N-(4-cyanophenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide389.2 24

(3R,4R)-N-(3-cyanophenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide389.2 25

(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]-N-(2-phenylethyl)piperidine-1-carboxamide 392.2 26

(3R,4R)-N-(2-furylmethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide368.2 27

N-methyl-N-[(3R,4R)-4-methyl-1- (propylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 351.2 28

N-[(3R,4R)-1-(isopropylsulfonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine351.2 29

4-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}sulfonyl)benzonitrile 410.2 30

2-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}sulfonyl)benzonitrile 410.2 31

N-methyl-N-[(3R,4R)-4-methyl-1- (methylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 323.2 32

N-methyl-N-{(3R,4R)-4-methyl-1-[(trifluoromethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 377.2 33

N-methyl-N-[(3R,4R)-4-methyl-1-(pyridin-3-ylsulfonyl)piperidin-3-yl]-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine386.2 34

2-fluoro-5-({(3R,4R)-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}sulfonyl)benzonitrile 428.2 35

N-methyl-N-[(3R,4R)-4-methyl-1-(3-pyridin-3-ylpropanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 378.2 36

N-methyl-N-[(3R,4R)-4-methyl-1-(3,3,3-trifluoropropanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 355.2 37

N-methyl-N-[(3R,4R)-4-methyl-1-(tetrahydrofuran-2-ylcarbonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 343.2 38

(2R)-1-{(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-1-oxopropan-2-ol 317.2 39

(2S)-1-{(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-1-oxopropan-2-ol 317.2 40

N-methyl-N-[(3R,4R)-4-methyl-1-(3-phenylpropanoyl)piperidin-3-yl]-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine377.2 41

(3R,4R)-N-(4-cyanophenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carbothioamide405.2 42

N-methyl-N-{(3R,4R)-4-methyl-1-[(5-methylisoxazol-4-yl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 390.2 43

N-methyl-N-{(3R,4R)-4-methyl-1-[(1- methyl-1H-imidazol-4-yl)sulfonyl]piperidin-3-yl}-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine389.2 44

N-{(3R,4R)-1-[(3,5-dimethylisoxazol-4-yl)carbonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 368.2 45

(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]-N-2-thienylpiperidine-1-carboxamide 370.2 46

N-[(3R,4R)-1-(isoxazol-5-ylcarbonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine340.2 47

N-{(3R,4R)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 403.2 48

N-[4-methyl-5-({(3R,4R)-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)-1,3- thiazol-2-yl]acetamide 463.2 49

N-{(3R,4R)-1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 420.2 50

N-methyl-N-{(3R,4R)-4-methyl-1-[(1,3,5- trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidin-3-yl}-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine417.2 51

N-{(3R,4R)-1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 404.2 52

N-methyl-N-{(3R,4R)-4-methyl-1-[(pyridin-4-ylmethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 400.2 53

N-methyl-N-{(3R,4R)-4-methyl-1-[(pyridin-3-ylmethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 400.2 54

N-methyl-N-{(3R,4R)-4-methyl-1-[(pyridin-2-ylmethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 400.2 55

4-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}sulfonyl)benzonitrile 410.2 56

(3R,4R)-N-(4-cyanophenyl)-N,4-dimethyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide403.2 57

(3R,4R)-N-(4-cyanophenyl)-N-ethyl-4- methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1- carboxamide 417.2 58

(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]-N-1,3-thiazol-2-ylpiperidine-1-carboxamide 371.2 59

(3R,4R)-4-methyl-N-(3-methylisoxazol-5-yl)-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide 369.2 60

3-chloro-4-({(3R,4R)-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}sulfonyl)benzonitrile 444.1 61

(3R,4R)-4-methyl-N-(5-methylisoxazol-3-yl)-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide 369.2 62

(3R,4R)-N-isoxazol-3-yl-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide 355.2 63

N-methyl-N-{(3R,4R)-4-methyl-1-[(5-pyridin-3-yl-2-thienyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 468.2 64

(3R,4R)-N-(3-cyano-2-thienyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide395.2 65

(3R,4R)-N-1,3-benzothiazol-2-yl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide421.2 66

N-[(3R,4R)-1-(2,3-dihydro-1H-indol-1-ylcarbonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 390.2 67

N-methyl-N-{(3R,4R)-4-methyl-1-[(methylthio)acetyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 333.2 68

(3R,4R)-N-(4,5-dihydro-1,3-thiazol-2-yl)-4-methyl-3-[methyl(1H-pyrrolo[2,3- b]pyridin-4-yl)amino]piperidine-1-carboxamide 373.2 69

(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]-N-(1,3-thiazol-2-ylmethyl)piperidine-1- carboxamide 385.2 70

1-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)piperidine-4-carbonitrile 381.2 71

1-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)piperidine-3-carbonitrile 381.2 72

1-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)pyrrolidine-3-carbonitrile 384.2 73

(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]-N-(3-thienylmethyl)piperidine-1-carboxamide 384.2 74

(3R,4R)-N-(2-benzothien-1-ylmethyl)-4- methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1- carboxamide 434.2 75

(3R,4R)-N-(1,3-benzothiazol-2-ylmethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3- b]pyridin-4-yl)amino]piperidine-1-carboxamide 435.2 76

N-[(3R,4R)-1-(3-furylacetyl)-4- methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 353.2 77

3-(2-{(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-2-oxoethyl)-1,3- thiazolidine-2,4-dione 402.278

3-(2-{(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-2-oxoethyl)-1,3- benzothiazol-2(3H)-one 436.279

(3R,4R)-N-[5-(cyanomethyl)-4,5-dihydro,-1,3-thiazol-2-yl]-3-[methyl-(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]-4-methyl-piperidine-1-carboxamide 412.2 80

(3S)-1-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)pyrrolidine-3-carbonitrile 367.2 81

(3R)-1-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)pyrrolidine-3-carbonitrile 367.2 82

1-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)-4- phenylpiperidine-4-carbonitrile457.2 83

N-methyl-N-((3R,4R)-4-methyl-1-{[3- (trifluoromethyl)pyrrolidin-1-yl]carbonyl}piperidin-3-yl)-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine410.2 84

1-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)azetidine-3-carbonitrile 353.2 85

4-methyl-1-({(3R,4R)-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)pyrrolidine-3-carbonitrile 381.2 86

1-({(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)pyrrolidine-3,4-dicarbonitrile 392.287

3-methyl-1-({(3R,4R)-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)pyrrolidine-3-carbonitrile 381.2 88

(3R,4R)-N-(2-cyanoethyl)-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide 341.2 89

4-methoxy-1-({(3R,4R)-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1- yl}carbonyl)pyrrolidine-3-carbonitrile 397.2 90

N-{(3R,4R)-1-[(2R)-2-aminopropanoyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine316.1 91

N-[(3R,4R)-1-(aminoacetyl)-4- methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 302.1 92

1-(2-{(3R,4R)-4-methyl-3-[methyl(1H- pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-2- oxoethyl)piperidine-4-carbonitrile 395.1 93

N-methyl-N-[(3R,4R)-4-methyl-1-(1,3-thiazol-4-ylcarbonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine bis (trifluoroacetate) 356.1 94

4-(2-2S-{[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amino]-methyl}-pyrrolidin- 1-yl-sulfonyl)-benzonitriletrifluoroacetate 396.1 95

N-[(1-methanesulfonyl-2S-pyrrolidin-2-yl)-methyl]-N-methyl-N-(1H-pyrrolo[2,3- b]pyridin-4-yl)-aminetrifluoroacetate 309.1 96

3-((2S)-2-{[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]methyl}pyrrolidin-1- yl)-3-oxopropanenitriletrifluoroacetate 298.1 97

Methyl 3-[({(3R,4R)-4-methyl-3- [methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-yl}carbonyl)- amino]benzoate 422.1 98

(3R,4R)-N-(4-trifluoromethoxyphenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3- b]pyridin-4-yl)amino]piperidine-1-carboxamide 448.1 99

(3R,4R)-N-(4-fluorophenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide382.1 100

(3R,4R)-N-(3-fluorophenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide382.1 101

(3R,4R)-N-(2-fluorophenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide382.1 102

(3R,4R)-N-(4-trifluoromethylphenyl)-4- methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1- carboxamide 432.1 103

(3R,4R)-N-(2-methoxyphenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4- yl)amino]piperidine-1-carboxamide394.1 104

(3R,4R)-4-methyl-N-(4-methylphenyl)-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)- amino]piperidine-1-carboxamide378.1 105

N-methyl-N-{(3R,4R)-4-methyl-1-[4-(pyridin-2-yloxy)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 478.1 106

N-methyl-N-{(3R,4R)-4-methyl-1-[4-(1,3-oxazol-5-yl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 452.1 107

N-methyl-N-{(3R,4R)-4-methyl-1-[5-(1,3-oxazol-5-yl)thienyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 458.1 108

N-methyl-N-{(3R,4R)-4-methyl-1-[(6-phenoxy-pyridin-3-yl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 478.1 109

N-{(3R,4R)-1-[(2,6- dichlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl- N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine453.1 110

N-{(3R,4R)-1-[(4-fluorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 403.1 111

N-{(3R,4R)-1-[(3-fluorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 403.1 112

N-{(3R,4R)-1-[(2-fluorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 403.1 113

N-{(3R,4R)-4-methyl-1-[4- (trifluoromethyl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 453.1 114

N-{(3R,4R)-4-methyl-1-[3- (trifluoromethyl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 453.1 115

N-{(3R,4R)-4-methyl-1-[2- (trifluoromethyl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)- amine 453.1 116

N-{(3R,4R)-1-[(4- methoxyphenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine415.1 117

N-{(3R,4R)-1-[(3- methoxyphenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H- pyrrolo[2,3-b]pyridin-4-yl)-amine415.1 118

N-methyl-N-{(3R,4R)-4-methyl-1-[(4-methylphenyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 399.1 119

N-methyl-N-{(3R,4R)-4-methyl-1-[(3-methylphenyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 399.1 120

N-methyl-N-{(3R,4R)-4-methyl-1-[(2-methylphenyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 399.1 121

N-{(3R,4R)-1-[(4-chlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 419.1 122

N-{(3R,4R)-1-[(3-chlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 419.1 123

N-{(3R,4R)-1-[(2-chlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine 419.1

Example A

In Vitro JAK Assay

Compounds herein were tested for inhibitory activity of Jak targetsaccording to the following in vitro assay described in Park et al.,Analytical Biochemistry 1999, 269, 94-104. The catalytic domains ofhuman Jak1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a.781-1124) with an N-terminal His tag were expressed using baculovirus ininsect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3was assayed by measuring the phosphorylation of a biotinylated peptide.The phosphorylated peptide was detected by homogenous time resolvedfluorescence (HTRF). IC₅₀s of compounds were measured for each kinase inthe reactions that contain the enzyme, ATP and 500 nM peptide in 50 mMTris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/ml (0.01%)BSA. The ATP concentration in the reactions was 90 μM for Jak1, 30 μMfor Jak2 and 3 μM for Jak3. Reactions were carried out at roomtemperature for 1 hr and then stopped with 20 μL 45 mM EDTA, 300 nMSA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, Mass.).Binding to the Europium labeled antibody took place for 40 minutes andHTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston,Mass.). Compounds having an IC₅₀ of 10 μM or less for any of theabove-mentioned Jak targets were considered active.

Example B

Murine DTH Model for Dermatitis

Model

Certain compounds herein were also tested for their efficacies (ofinhibiting Jak targets) in the T-cell driven murine delayedhypersysitivity test model. The murine skin contact delayed-typehypersensitivity (DTH) response is considered to be a valid model ofclinical contact dermatitis, and other T-lymphocyte mediated immunedisorders of the skin, such as psoriasis (Immunol Today. 1998 January;19(1):37-44). Murine DTH shares multiple characteristics with psoriasis,including the immune infiltrate, the accompanying increase ininflammatory cytokines, and keratinocyte hyperproliferation.Furthermore, many classes of agents that are efficacious in treatingpsoriasis in the clinic are also effective inhibitors of the DTHresponse in mice (Agents Actions. 1993 January; 38(1-2):116-21).

Systemic Administration

Test compound3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-piperidin-1-yl}-3-oxo-propionitrile(see, e.g., WO 01/42246, WO 02/00661, or WO 03/48162) was administeredcontinuously using mini-osmotic pumps to deliver the compound at 150mg/kg/d. The inflammatory response was monitored by measuring the earthickness prior to and after immune challenge. Differences in earthickness were calculated for each mouse and then averaged for thegroup. Comparisons were made between vehicle and the treated groups inthe context of the negative controls (challenged without sensitization)and therapeutic positive control mice (treated with dexamethasone orother efficacious agent). The test compound inhibited ear swelling by95% and histological analysis of hematoxolyin and eosin stained tissuesections confirmed a near complete inhibition of ear swelling.

Topical Administration

A further murine DTH experiment was conducted by treating mice with3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-piperidin-1-yl}-3-oxo-propionitrileeither systemically or topically (3%, BID) after the sensitization phasewas complete. As was observed with systemic administration during boththe sensitization and challenge phases, treatment with the test compoundsignificantly (>50%) inhibited ear swelling when administered by eitherroute during the challenge phase (FIG. 1).

To determine if topical administration of the test compound wassufficient to inhibit activation of the Jak-STAT pathway,immunohistochemistry was carried out on fixed tissues. Formalin fixedand paraffin embedded ear sections were subjected to immunohistochemicalanalysis using an antibody that specifically interacts with STAT3 (clone58E12, Cell Signaling Technologies) Both systemic and topicaladministration of the test compound visibly reduced the number ofinfiltrating cells and inhibited phosphorylation of STAT3 in all celltypes even when administered after the sensitization phase.

In order to determine the impact of topically applied test compound3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-piperidin-1-yl}-3-oxo-propionitrile(3%) or dexamtheasone (0.1%) on the DTH transcriptional response, rodentear tissue tissues were profiled 48 hr post-challenge using Agilent60-mer oligonucleotide high-density DNA microarray analysis. Downstreamimage segmentation was performed using Agilent Feature Extractorsoftware and data analysis was performed using Rosetta Resolver v 4.0.Two dimensional clustering was performed using an error-weightedagglomerative clustering algorithm (Rosetta Biosoftware) using averagelink heuristics and Pearson correlation similarity measures. Statisticalsignificance of all expression data (P<0.01 for inclusion inagglomerative clusters) were error weighted using the duplicatefluorescent-dye reversal data sets as well as an empirical error modelbased on historical Agilent 60-mer microarray data. Vehicle and drugtreated groups were individually compared to the negative control(challenged unsensitized animals) which was used as a baseline.Differences between the respective treated groups and the baseline werethen compared to each other. It was demonstrated that a clinicallyefficacious treatment for psoriasis (dexamtheasone) produced similartranscriptional changes as did the test compound, both qualitatively andquantitatively, in the DTH model (FIG. 2).

Example C

In Vitro Mutant Jak (mtJAK) Assay

Compounds herein can be tested for inhibitory activity of mutant Jak(mtjak) targets according to the following in vitro assay described inPark et al., Analytical Biochemistry 1999, 269, 94-104 with variationsdescribed herein. Activating mutations, residing anywhere within thecoding region of the Jak DNA, cDNA, or mRNA, can be introduced tonucleic acid sequences encoding for Jaks using standard molecularbiology techniques (e.g. nucleotide mutagenesis) familiar to thoseschooled in the art. This includes, but is not limited to mutations inthe codon for a.a. 617 that results in a substitution of the wild-typevaline with a phenylalanine. The kinase domain (a.a. 828-1132), thepseudo-kinase and kinase domains (a.a. 543-827 and 828-1132,respectively), or the entire Jak protein, with an N-terminal His tag,can be expressed using baculovirus in insect cells and purified. Similarstrategies can be employed to generate mutant Jak1, Jak3, or Tyk2. Thecatalytic activity of Jak can then be assayed by measuring thephosphorylation of a biotinylated peptide. The phosphorylated peptidecan be detected by homogenous time resolved fluorescence (HTRF) usingsuitable and optimized buffers and concentrations of ATP, peptide,kinase, etc. Compounds having an IC₅₀ of about 10 μM or less for any ofthe above-mentioned Jak targets will typically be considered active.

Example D

Cell-Based mtJAK Assay

As a complement to the in vitro kinase assay, cells expressing themutated form(s) of Jak may be identified (e.g. HEL cells, ATCC) orconstructed (by transfection, infection, or similar technique tointroduce the nucleic acid encoding for the Jak) using techniquesfamiliar to those schooled in the art. Cells may then be treated withcompounds for various times (usually between 0 and 4 hours) andcollected for protein extraction using methods familiar to thoseschooled in the art. Cellular protein extracts can then be analyzed forboth total and phospho-Jak using, for example, the following antibodies:total Jak1 (Cell Signaling, #9138), phospho-Jak1 (Abcam, #ab5493), totalJak2 (Upstate #06-255), phospho-Jak (Cell Signaling, #3771), total Jak3(Santa Cruz, #sc-513), phospho-Jak3 (Santa Cruz, #sc-16567), total Tyk2(Santa Cruz #sc-169), phospho-Tyk2 (Cell Signal #9321), andphospho-tyrosine (Upstate, #05-231). Methodologies to perform theseanalyses include but are not limited to immunoblotting,immunoprecipitation, ELISA, RIA, immunocytochemistry, and FACS.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication, including all patents, patent applications, and non-patentliterature, is incorporated herein by reference in its entirety.

1. A compound of Formula I:

or pharmaceutically acceptable salt form or prodrug thereof, wherein:R¹, R², and R³ are each, independently, H, halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), orS(O)₂NR^(c)R^(d); R⁴ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,S(O)₂R⁹, SOR⁹, cycloalkyl, or heterocycloalkyl, wherein said C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, heterocycloalkyl are eachoptionally substituted with 1, 2 or 3 substituents selected from halo,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a)S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); R⁵ is 3-8 memberedcycloalkyl, 3-8 membered heterocycloalkyl, -L-(3-8 membered cycloalkyl),-L-(3-8 membered heterocycloalkyl), each substituted by one R⁶ and 0, 1or 2 R⁷; L is C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S,NR¹⁴, CO, COO, OCO, NR¹⁴C(O)O, CONR¹⁴, SO, SO₂, SONR¹⁴, SO₂NR¹⁴, orNR¹⁴CONR¹⁴; R⁶ is —W¹—W²—W³—W⁴—W⁵—W⁶—R¹³; W¹ is absent, C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl, heteroaryl, cycloalkyl orheterocycloalkyl, each optionally substituted by 1, 2 or 3 halo, CN,NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; W² is absent,C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S, NR¹², CO, COO,OCO, C(S), C(S)NR¹², —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹²,SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl,C₂₋₄ alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, OH,C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W³ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whereinsaid C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W⁴ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄alkynylenyl, O, S, NR¹², Co, COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹²,SO, SO₂, SONR¹², SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, are each optionally substituted by1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W⁵ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whereinsaid C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W⁶ is absent, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, O,S, NR¹², CO, COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹²,SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl are each optionally substituted by 1, 2 or 3 CN, NO₂, OH, ═NH,═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; R⁷ is halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″),—(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), or —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″); R⁹ is C₁₋₄ alkyl, aryl, heteroaryl,cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2,or 3 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′),OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(C′)C(O)R^(d′),NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), andS(O)₂NR^(c′)R^(d′); R¹² and R¹⁴ are each, independently, H or C₁₋₆ alkyloptionally substituted by 1, 2 or 3 substituents selected from OH, CN,NO₂, amino, (C₁₋₄ alkyl)amino, (C₂₋₈ dialkyl)amino, C₁₋₆ haloalkyl, C₁₋₆acyl, C₁₋₆ acyloxy, C₁₋₆ acylamino, —(C₁₋₆ alkyl)-CN, and —(C₁₋₆alkyl)-NO₂; R¹³ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″),NR^(c″)C(O)R^(d″)NR^(c″)C(O)OR^(a″)S(O)R^(b″), S(O)NR^(c″)R^(d″),S(O)₂R^(b″), S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂,—(C₁₋₆ alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″),—(C₁₋₆ alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″)—(C₁₋₆ alkyl)-S(O)₂R^(b″), or —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″), wherein each of said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl,halo, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″),NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″),S(O)₂R^(b″), S(O)₂NR^(C″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂,—(C₁₋₆ alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″),—(C₁₋₆ alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆(alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″); R^(a), R^(a′) and R^(a″) are each,independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R^(b), R^(b′)and R^(b″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;R^(c) and R^(d) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; or R^(c) and R^(d) together with the N atom to whichthey are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup; R^(c′) and R^(d′) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; or R^(c′) and R^(d′) together with the N atom to whichthey are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup; and R^(c″) and R^(d″) are each, independently, H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl,or cycloalkylalkyl; or R^(c″) and R^(d″) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup.
 2. The compound of claim 1 wherein R¹ is H.
 3. The compound ofclaim 1 wherein R² is H.
 4. The compound of claim 1 wherein R³ is H. 5.The compound of claim 1 wherein R⁴ is H or C₁₋₄ alkyl.
 6. The compoundof claim 1 wherein R⁴ is methyl.
 7. The compound of claim 1 wherein R⁵is 3-8 membered heterocycloalkyl substituted by one R⁶ and 0, 1 or 2 R⁷.8. The compound of claim 1 wherein R⁵ is 6-membered heterocycloalkylsubstituted by one R⁶ and 0, 1 or 2 R⁷.
 9. The compound of claim 1wherein R⁵ is piperidinyl substituted by one R⁶ and 0, 1 or 2R⁷.
 10. Thecompound of claim 1 wherein R⁵ is piperidin-3-yl substituted by one R⁶and 0, 1 or 2 R⁷.
 11. The compound of claim 10 wherein R⁶ is substitutedon the piperidinyl N-atom.
 12. The compound of claim 1 wherein R⁵ is-L-pyrrolidinyl; L is C₁₋₄ alkylenyl; and said pyrrolidinyl issubstituted by one R⁶ and 0, 1 or 2 R⁷.
 13. The compound of claim 1wherein R⁵ is -L-pyrrolidin-2-yl; L is C₁₋₄ alkylenyl and saidpyrrolidin-2-yl is substituted by one R⁶ and 0, 1 or 2 R⁷.
 14. Thecompound of claim 1 wherein W² is SO₂, CO, COO, C(S)NR¹², or CONR¹². 15.The compound of claim 1 wherein W² is SO₂, CO, COO, C(S)NH, CONH or—CON(C₁₋₄ alkyl)-.
 16. The compound of claim 1 wherein W² is SO₂ or CO.17. The compound of claim 1 wherein W³ is C₁₋₄ alkylenyl or cycloalkyl.18. The compound of claim 1 wherein R¹³ is C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl,halo, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″),NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″),S(O)₂R^(b″), S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂,—(C₁₋₆ alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″),—(C₁₋₆ alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)OR^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″).
 19. The compound of claim 1 wherein R¹³ isC₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl,halo, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″),NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″),S(O)₂R^(b″), S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂,—(C₁₋₆ alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″)—(C₁₋₆alkyl)-C(O)R^(b″),—(C₁₋₆ alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆alkyl)-OC(O)NR^(c″)R^(d″),—(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and—(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″).
 20. The compound of claim 1 wherein R¹³is C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, heteroaryl, halo, CN, OR^(a″), SR^(a″), C(O)R^(b″), C(O)OR^(a″),NR^(c″)C(O)R^(d″), S(O)₂R^(b″), and —(C₁₋₆ alkyl)-CN.
 21. The compoundof claim 1 wherein R¹³ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by1, 2, 3, 4 or 5 substituents independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, aryl, heteroaryl, halo, CN, OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, heteroaryloxy, aryloxy, —SC₁₋₆ alkyl, —C(O)—C₁₋₆ alkyl,—C(O)OC₁₋₆ alkyl, —S(O)₂C₁₋₆ alkyl, —NHC(O)—C₁₋₆ alkyl, and —(C₁₋₆alkyl)-CN.
 22. The compound of claim 1 where R¹³ is OH or CN.
 23. Thecompound of claim 1 wherein W¹ is absent, W² is CO or SO₂, W³ is C₁₋₄alkyleneyl or cycloalkyl, W⁴ is absent, W⁵ is absent, W⁶ is absent, andR¹³ is CN or OH.
 24. The compound of claim 1 wherein R⁶ is —W²—W³—R¹³.25. The compound of claim 1 wherein R⁶ is —CO—CH₂—CN.
 26. The compoundof claim 1 wherein R⁶ is —W²—R¹³.
 27. The compound of claim 1 wherein:R⁶ is —W²—R¹³; W² is SO₂, CO, COO, C(S)NR¹², or CONR¹²; and R¹³ is C₁₋₆alkyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl,each optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl,halo, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″),NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″),S(O)₂R^(b″), S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂,—(C₁₋₆ alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″),—(C₁₋₆ alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆alkyl)-OC(O)NR^(c″)R^(d″),—(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-S(O)₂R^(b″), and —(C₁₋₆ alkyl)-S(O)₂NR^(c″)R^(d″).
 28. Thecompound of claim 1 having the structure of Formula I-A:

wherein t is 0, 1 or
 2. 29. The compound of claim 28 wherein: W² is SO₂,CO, COO, C(S)NR¹², or CONR¹²; and R¹³ is C₁₋₆ alkyl, C₁₋₆ haloalkyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)NR^(c″)C(O)OR^(a″), —(C₁₋₆alkyl)-S(O)R^(b″),—(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆(alkyl)-S(O)₂NR^(c″)R^(d″).
 30. The compound of claim 1 having thestructure of Formula I-B:

wherein t1 is 0 or
 1. 31. The compound of claim 30 wherein R¹³ is C₁₋₆alkyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl,each optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,heteroaryl, halo, CN, OR^(a″), SR^(a″), C(O)R^(b″), C(O)OR^(a″),NR^(c″)C(O)R^(d″), S(O)₂R^(b″), and —(C₁₋₆ alkyl)-CN; W² is SO₂, CO,COO, C(S)NH, CONH or —CON(C₁₋₄ alkyl)-; and R⁴ is C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, S(O)₂R⁹, SOR⁹, cycloalkyl, or heterocycloalkyl,wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl,heterocycloalkyl are each optionally substituted with 1, 2 or 3substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).
 32. Acompound of claim 1 selected from:3-{3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile;3-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile;N-methyl-N-[(3R,4R)-4-methyl-1-(phenylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-[(3R,4R)-1-(methoxyacetyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-phenylpiperidine-1-carboxamide;(3R,4R)-N-benzyl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-ethyl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-isopropyl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-[(3R,4R)-1-isobutyryl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-[(3R,4R)-4-methyl-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-[(3R,4R)-1-acetyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-[(3R,4R)-4-methyl-1-(3-methylbutanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-[(3R,4R)-1-benzoyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;(3R,4R)-N,N,4-trimethyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;4-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl)}carbonyl)benzonitrile;N-[(3R,4R)-1-(cyclopropylcarbonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-[(3R,4R)-1-isonicotinoyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(1-acetylpiperidin-4-yl)carbonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;Phenyl(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxylate;Methyl(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxylate;N-methyl-N-[(3R,4R)-4-methyl-1-(trifluoroacetyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-[(3R,4R)-1-(2-furoyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;(3R,4R)-N-(4-cyanophenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-(3-cyanophenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-(2-phenylethyl)piperidine-1-carboxamide;(3R,4R)-N-(2-furylmethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-methyl-N-[(3R,4R)-4-methyl-1-(propylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-[(3R,4R)-1-(isopropylsulfonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;4-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile;2-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile;N-methyl-N-[(3R,4R)-4-methyl-1-(methylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(trifluoromethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-[(3R,4R)-4-methyl-1-(pyridin-3-ylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;2-fluoro-5-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile;N-methyl-N-[(3R,4R)-4-methyl-1-(3-pyridin-3-ylpropanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-[(3R,4R)-4-methyl-1-(3,3,3-trifluoropropanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-[(3R,4R)-4-methyl-1-(tetrahydrofuran-2-ylcarbonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;(2R)-1-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-1-oxopropan-2-ol;(2S)-1-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-1-oxopropan-2-ol;N-methyl-N-[(3R,4R)-4-methyl-1-(3-phenylpropanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;(3R,4R)-N-(4-cyanophenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carbothioamide;N-methyl-N-{(3R,4R)-4-methyl-1-[(5-methylisoxazol-4-yl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(3,5-dimethylisoxazol-4-yl)carbonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-2-thienylpiperidine-1-carboxamide;N-[(3R,4R)-1-(isoxazol-5-ylcarbonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-[4-methyl-5-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)-1,3-thiazol-2-yl]acetamide;N-{(3R,4R)-1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(pyridin-4-ylmethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(pyridin-3-ylmethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(pyridin-2-ylmethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;4-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile;(3R,4R)-N-(4-cyanophenyl)-N,4-dimethyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-(4-cyanophenyl)-N-ethyl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-1,3-thiazol-2-ylpiperidine-1-carboxamide;(3R,4R)-4-methyl-N-(3-methylisoxazol-5-yl)-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;3-chloro-4-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile;(3R,4R)-4-methyl-N-(5-methylisoxazol-3-yl)-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-isoxazol-3-yl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-methyl-N-{(3R,4R)-4-methyl-1-[(5-pyridin-3-yl-2-thienyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;(3R,4R)-N-(3-cyano-2-thienyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-1,3-benzothiazol-2-yl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-[(3R,4R)-1-(2,3-dihydro-1H-indol-1-ylcarbonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(methylthio)acetyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;(3R,4R)-N-(4,5-dihydro-1,3-thiazol-2-yl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-(1,3-thiazol-2-ylmethyl)piperidine-1-carboxamide;1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)piperidine-4-carbonitrile;1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)piperidine-3-carbonitrile;1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile;(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-(3-thienylmethyl)piperidine-1-carboxamide;(3R,4R)-N-(2-benzothien-1-ylmethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-(1,3-benzothiazol-2-ylmethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-[(3R,4R)-1-(3-furylacetyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;3-(2-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-2-oxoethyl)-1,3-thiazolidine-2,4-dione;3-(2-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-2-oxoethyl)-1,3-benzothiazol-2(3H)-one;(3R,4R)-N-[5-(cyanomethyl)-4,5-dihydro,-1,3-thiazol-2-yl]-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-4-methyl-piperidine-1-carboxamide;(3S)-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile;(3R)-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile;1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)-4-phenylpiperidine-4-carbonitrile;N-methyl-N-((3R,4R)-4-methyl-1-{[3-(trifluoromethyl)pyrrolidin-1-yl]carbonyl}piperidin-3-yl)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)azetidine-3-carbonitrile;4-methyl-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile;1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3,4-dicarbonitrile;3-methyl-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile;(3R,4R)-N-(2-cyanoethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;4-methoxy-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile;N-{(3R,4R)-1-[(2R)-2-aminopropanoyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-[(3R,4R)-1-(aminoacetyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;1-(2-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-2-oxoethyl)piperidine-4-carbonitrile;N-methyl-N-[(3R,4R)-4-methyl-1-(1,3-thiazol-4-ylcarbonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-aminebis (trifluoroacetate);4-(2-2S-{[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amino]-methyl}-pyrrolidin-1-yl-sulfonyl)-benzonitriletrifluoroacetate;N-[(1-methanesulfonyl-2S-pyrrolidin-2-yl)-methyl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-aminetrifluoroacetate;3-((2S)-2-{[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]methyl}pyrrolidin-1-yl)-3-oxopropanenitriletrifluoroacetate; Methyl3-[({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-yl}carbonyl)-amino]benzoate;(3R,4R)-N-(4-trifluoromethoxyphenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-(4-fluorophenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-(3-fluorophenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-(2-fluorophenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-(4-trifluoromethylphenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-N-(2-methoxyphenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-4-methyl-N-(4-methylphenyl)-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)-amino]piperidine-1-carboxamide;N-methyl-N-{(3R,4R)-4-methyl-1-[4-(pyridin-2-yloxy)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[4-(1,3-oxazol-5-yl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[5-(1,3-oxazol-5-yl)thienyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(6-phenoxy-pyridin-3-yl)sulfonyl]piperidin-3-yl}-(1H-pyrrolo[2,3-b]pyridin-4-yl)amine;N-{(3R,4R)-1-[(2,6-dichlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(4-fluorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(3-fluorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(2-fluorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-4-methyl-1-[4-(trifluoromethyl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-4-methyl-1-[3-(trifluoromethyl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-4-methyl-1-[2-(trifluoromethyl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(4-methoxyphenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(3-methoxyphenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(4-methylphenyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(3-methylphenyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-methyl-N-{(3R,4R)-4-methyl-1-[(2-methylphenyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(4-chlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;N-{(3R,4R)-1-[(3-chlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine;andN-{(3R,4R)-1-[(2-chlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine,or a pharmaceutically acceptable salt thereof.
 33. A compositioncomprising a compound of claim 1, or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 34. A method ofmodulating an activity of JAK comprising contacting JAK with a compoundof claim 1, or pharmaceutically acceptable salt thereof.
 35. The methodof claim 34 wherein said JAK is in a cell.
 36. The method of claim 34wherein said JAK is JAK1, JAK2, JAK3 or TYK2.
 37. The method of claim 34wherein said JAK is JAK1 or JAK2.
 38. The method of claim 34 whereinsaid JAK is JAK2.
 39. The method of claim 34 wherein said modulating isinhibiting.
 40. The method of claim 34 wherein said compound is aselective inhibitor of JAK2 over JAK1, JAK2, JAK3 and TYK2.
 41. A methodof treating a disease in a patient, wherein said disease is associatedwith JAK activity, comprising administering to said patient atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 42. The method of claim 41wherein said disease is allograft rejection or graft versus hostdisease.
 43. The method of claim 41 wherein said disease is anautoimmune disease.
 44. The method of claim 43 wherein said autoimmunedisease is a skin disorder, multiple sclerosis, rheumatoid arthritis,juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatorybowel disease, Crohn's disease, or autoimmune thyroid disorder.
 45. Themethod of claim 41 wherein said disease is a viral disease.
 46. Themethod of claim 45 wherein said viral disease is Epstein Barr Virus(EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicell-Zoster Virus(VZV) or Human Papilloma Virus (HPV).
 47. The method of claim 41 whereinsaid disease is cancer.
 48. The method of claim 47 wherein said canceris prostate cancer, lymphoma, leukemia, or multiple myeloma.
 49. Themethod of claim 47 wherein said cancer is multiple myeloma.
 50. Apharmaceutical composition for topical administration comprising acompound of Formula II:

or pharmaceutically acceptable salt form or prodrug thereof, wherein: Ais N or CR¹; R¹, R², and R³ are each, independently, H, halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), or S(O)₂NR^(c)R^(d); R⁴ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, S(O)₂R⁹, SOR⁹, cycloalkyl, or heterocycloalkyl, wherein saidC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, heterocycloalkyl areeach optionally substituted with 1, 2 or 3 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b) and S(O)₂NR^(c)R^(d); R⁵ is 3-8 memberedcycloalkyl, 3-8 membered heterocycloalkyl, -L-(3-8 membered cycloalkyl),-L-(3-8 membered heterocycloalkyl), each substituted by one R⁶ and 0, 1or 2 R⁷; L is C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S,NR¹⁴, CO, COO, OCO, NR¹⁴C(O)O, CONR¹⁴, SO, SO₂, SONR¹⁴, SO₂NR¹⁴, orNR¹⁴CONR₁₄; R⁶ is —W¹—W²—W³—W⁴—W⁵—W⁶—R¹³; W¹ is absent, C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl, heteroaryl, cycloalkyl orheterocycloalkyl, each optionally substituted by 1, 2 or 3 halo, CN,NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; W² is absent,C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S, NR¹², CO, COO,OCO, C(S), C(S)NR¹², —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹²,SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl,C₂₋₄ alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, OH,C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W³ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whereinsaid C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W⁴ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄alkynylenyl, O, S. NR¹², CO, COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹²,SO, SO₂, SONR¹², SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, are each optionally substituted by1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W⁵ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whereinsaid C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W⁶ is absent, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, O,S, NR¹², CO, COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹²,SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl are each optionally substituted by 1, 2 or 3 CN, NO₂, OH, ═NH,═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; R⁷ is halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), or —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″); R⁹ is C₁₋₄ alkyl, aryl, heteroaryl,cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2,or 3 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′),OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′),NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), andS(O)₂NR^(c′)R^(d′); R¹² and R¹⁴ are each, independently, H or C₁₋₆ alkyloptionally substituted by 1, 2 or 3 substituents selected from OH, CN,NO₂, amino, (C₁₋₄ alkyl)amino, (C₂₋₈ dialkyl)amino, C₁₋₆ haloalkyl, C₁₋₆acyl, C₁₋₆ acyloxy, C₁₋₆ acylamino, —(C₁₋₆ alkyl)-CN, and —(C₁₋₆alkyl)-NO₂; R¹³ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), or—(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″), wherein each of said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl,halo, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″),NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″),S(O)₂R^(b″), S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂,—(C₁₋₆ alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″),—(C₁₋₆ alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″); R^(a), R^(a′) and R^(a″) are each,independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R^(b), R^(b′)and R^(b″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;R^(c) and R^(d) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; or R^(c) and R^(d) together with the N atom to whichthey are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup; R^(c′) and R^(d′) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; or R^(c′) and R^(d′) together with the N atom to whichthey are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup; and R^(c″) and R^(d″) are each, independently, H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl,or cycloalkylalkyl; or R^(c″) and R^(d″) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup.
 51. The composition of claim 50 wherein said topicaladministration comprises transdermal administration.
 52. The compositionof claim 50 which is in the form of a transdermal patch, ointment,lotion, cream, or gel.
 53. The composition of claim 50 wherein A is CR¹.54. The composition of claim 50 wherein A is N.
 55. A method of treatinga skin disorder in a patient comprising topically administering to saidpatient a therapeutically effective amount of a compound of Formula II:

or pharmaceutically acceptable salt form or prodrug thereof, wherein: Ais N or CR¹; R¹, R², and R³ are each, independently, H, halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), or S(O)₂NR^(c)R^(d); R⁴ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, S(O)₂R⁹, SOR⁹, cycloalkyl, or heterocycloalkyl, wherein saidC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, heterocycloalkyl areeach optionally substituted with 1, 2 or 3 substituents selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); R⁵ is 3-8 memberedcycloalkyl, 3-8 membered heterocycloalkyl, -L-(3-8 membered cycloalkyl),-L-(3-8 membered heterocycloalkyl), each substituted by one R⁶ and 0, 1or 2 R⁷; L is C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S,NR¹⁴, CO, COO, OCO, NR¹⁴C(O)O, CONR¹⁴, SO, SO₂, SONR¹⁴, SO₂NR¹⁴, orNR¹⁴CONR¹⁴; R⁶ is —W¹—W²—W³—W⁴—W⁵—W⁶—R¹³; W¹ is absent, C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl, heteroaryl, cycloalkyl orheterocycloalkyl, each optionally substituted by 1, 2 or 3 halo, CN,NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; W² is absent,C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, O, S, NR¹², Co, COO,OCO, C(S), C(S)NR¹², —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹²,SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl,C₂₋₄ alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, OH,C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W³ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whereinsaid C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W⁴ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄alkynylenyl, O, S, NR¹², CO, COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹²,SO, SO₂, SONR¹², SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkylenyl,C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, are each optionally substituted by1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W⁵ is absent, C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whereinsaid C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by1, 2 or 3 halo, CN, NO₂, OH, ═NH, ═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈dialkylamino; W⁶ is absent, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, O,S, NR¹², CO, COO, OCO, —C(═N—CN)—, NR¹²C(O)O, CONR¹², SO, SO₂, SONR¹²,SO₂NR¹², or NR¹²CONR¹², wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl are each optionally substituted by 1, 2 or 3 CN, NO₂, OH, ═NH,═NOH, ═NO—(C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino; R⁷ is halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″) S(O)NR^(c″)R^(d″) S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″),—(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-S(O)₂R^(b″), or —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″); R⁹ is C₁₋₄ alkyl, aryl, heteroaryl,cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2,or 3 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′),OC(O)R^(b′), OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(d′),NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′), andS(O)₂NR^(c′)R^(d′); R¹² and R¹⁴ are each, independently, H or C₁₋₆ alkyloptionally substituted by 1, 2 or 3 substituents selected from OH, CN,NO₂, amino, (C₁₋₄ alkyl)amino, (C₂₋₈ dialkyl)amino, C₁₋₆ haloalkyl, C₁₋₆acyl, C₁₋₆ acyloxy, C₁₋₆ acylamino, —(C₁₋₆ alkyl)-CN, and —(C₁₋₆alkyl)-NO₂; R¹³ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(d″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″),S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂, —(C₁₋₆alkyl)-OR^(a″), —(C₁₋₆alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″), —(C₁₋₆alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), or —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(d″), wherein each of said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl,halo, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″),NR^(c″)C(O)R^(d″), NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″),S(O)₂R^(b″), S(O)₂NR^(c″)R^(d″), —(C₁₋₆ alkyl)-CN, —(C₁₋₆ alkyl)-NO₂,—(C₁₋₆ alkyl)-OR^(a″), —(C₁₋₆ alkyl)-SR^(a″), —(C₁₋₆ alkyl)-C(O)R^(b″),—(C₁₋₆ alkyl)-C(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-C(O)OR^(a″), —(C₁₋₆alkyl)-OC(O)R^(b″), —(C₁₋₆ alkyl)-OC(O)NR^(c″)R^(d″), —(C₁₋₆alkyl)-NR^(c″)R^(d″), —(C₁₋₆ alkyl)-NR^(c″)C(O)R^(d″), —(C₁₋₆alkyl)-NR^(c″)C(O)OR^(a″), —(C₁₋₆ alkyl)-S(O)R^(b″), —(C₁₋₆alkyl)-S(O)NR^(c″)R^(d″), —(C₁₋₆ alkyl)-S(O)₂R^(b″), and —(C₁₋₆alkyl)-S(O)₂NR^(c″)R^(b″); R^(a), R^(a′) and R^(a″) are each,independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R^(b), R^(b′)and R^(b″) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;R^(c) and R^(d) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; or R^(c) and R^(d) together with the N atom to whichthey are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup; R^(c′) and R^(d′) are each, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; or R^(c′) and R^(d′) together with the N atom to whichthey are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup; and R^(c″) and R^(d″) are each, independently, H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl,or cycloalkylalkyl; or R^(c″) and R^(d″) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup.
 56. The method of claim 55 wherein said skin disorder is atopicdermatitis or psoriasis.
 57. The method of claim 55 wherein said skindisorder is skin sensitization, skin irritation, skin rash, contactdermatitis or allergic contact sensitization.
 58. The method of claim 55wherein said compound of Formula II is administered in the form of atransdermal patch, ointment, lotion, cream, or gel.
 59. The method ofclaim 55 wherein A is CR¹.
 60. The method of claim 55 wherein A is N.